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      Asymmetric and symmetric dimethylarginines and mortality in patients with hematological malignancies—A prospective study

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          Abstract

          The study was designed to determine the associations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginines plasma concentrations with all-cause mortality in patients with hematological malignancies. 33 patients with acute myeloid leukemia (AML), 31 patients with non-Hodgkin’s lymphoma (nHL), 32 patients with chronic lymphocytic leukemia (CLL) and 48 patients without malignancy were enrolled into the study. Each patient was followed until death or for at least 14.5 months (range: 14.5–53). Median ADMA and SDMA were significantly elevated in AML, nHL and CLL compared to controls (ADMA: 1.36, 1.24, 1.03, 0.55 μmol/l respectively, p<0.0001; SDMA: 0.86, 0.76, 0.71, 0.52 μmol/l respectively, p<0.0001). High ADMA and SDMA were associated with increased risk for all-cause mortality in CLL group (Hazard ratio (HR) for ADMA: 3.05, 95% CI:1.58–5.88, p = 0.001; HR for SDMA: 4.71, 95% CI:1.91–11.58, p = 0.001). Our study suggests that ADMA and SDMA could be novel prognostic factors for all-cause mortality in CLL patients.

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          Nitric oxide and cancer: a review

          Nitric oxide (NO), is a ubiquitous, water soluble, free radical gas, which plays key role in various physiological as well as pathological processes. Over past decades, NO has emerged as a molecule of interest in carcinogenesis and tumor growth progression. However, there is considerable controversy and confusion in understanding its role in cancer biology. It is said to have both tumoricidal as well as tumor promoting effects which depend on its timing, location, and concentration. NO has been suggested to modulate different cancer-related events including angiogenesis, apoptosis, cell cycle, invasion, and metastasis. On the other hand, it is also emerging as a potential anti-oncogenic agent. Strategies for manipulating in vivo production and exogenous delivery of this molecule for therapeutic gain are being investigated. However, further validation and experimental/clinical trials are required for development of novel strategies based on NO for cancer treatment and prevention. This review discusses the range of actions of NO in cancer by performing an online MEDLINE search using relevant search terms and a review of the literature. Various mechanisms by which NO acts in different cancers such as breast, cervical, gastric,colorectal, and head and neck cancers are addressed. It also offers an insight into the dichotomous nature of NO and discusses its novel therapeutic applications for cancer prevention and treatment.
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            The discovery of nitric oxide and its role in vascular biology.

            Nitric oxide (NO) is a relative newcomer to pharmacology, as the paper which initiated the field was published only 25 years ago. Nevertheless its impact is such that to date more than 31,000 papers have been published with NO in the title and more than 65,000 refer to it in some way. The identification of NO with endothelium-derived relaxing factor and the discovery of its synthesis from L-arginine led to the realisation that the L-arginine: NO pathway is widespread and plays a variety of physiological roles. These include the maintenance of vascular tone, neurotransmitter function in both the central and peripheral nervous systems, and mediation of cellular defence. In addition, NO interacts with mitochondrial systems to regulate cell respiration and to augment the generation of reactive oxygen species, thus triggering mechanisms of cell survival or death. This review will focus on the role of NO in the cardiovascular system where, in addition to maintaining a vasodilator tone, it inhibits platelet aggregation and adhesion and modulates smooth muscle cell proliferation. NO has been implicated in a number of cardiovascular diseases and virtually every risk factor for these appears to be associated with a reduction in endothelial generation of NO. Reduced basal NO synthesis or action leads to vasoconstriction, elevated blood pressure and thrombus formation. By contrast, overproduction of NO leads to vasodilatation, hypotension, vascular leakage, and disruption of cell metabolism. Appropriate pharmacological or molecular biological manipulation of the generation of NO will doubtless prove beneficial in such conditions.
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              Asymmetric Dimethylarginine (ADMA): A Novel Risk Factor for Endothelial Dysfunction : Its Role in Hypercholesterolemia

              Background —Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase. Because endothelial NO elaboration is impaired in hypercholesterolemia, we investigated whether plasma concentrations of ADMA are elevated in young, clinically asymptomatic hypercholesterolemic adults. We further studied whether such elevation of ADMA levels was correlated with impaired endothelium-dependent, NO-mediated vasodilation and urinary nitrate excretion. In a randomized, double-blind, placebo-controlled study, we investigated whether these changes could be reversed with exogenous l -arginine. Methods and Results —We measured plasma levels of l -arginine, ADMA, and symmetrical dimethylarginine (SDMA) by high-performance liquid chromatography in 49 hypercholesterolemic (HC) and 31 normocholesterolemic (NC) humans. In 8 HC subjects, endothelium-dependent forearm vasodilation was assessed before and after an intravenous infusion of l -arginine or placebo and compared with 8 NC control subjects. ADMA levels were significantly elevated by >100% (2.17±0.15 versus 1.03±0.09 μmol/L; P <0.05) in HC subjects compared with NC adults. l -Arginine levels were similar, resulting in a significantly decreased l -arginine/ADMA ratio in HC subjects (27.7±2.4 versus 55.7±5.4; P <0.05). In 8 HC subjects, intravenous infusion of l -arginine significantly increased the l -arginine/ADMA ratio and normalized endothelium-dependent vasodilation and urinary nitrate excretion. ADMA levels were inversely correlated with endothelium-mediated vasodilation ( R =0.762, P <0.01) and urinary nitrate excretion rates ( R =0.534, P <0.01). Conclusions —We find that ADMA is elevated in young HC individuals. Elevation of ADMA is associated with impaired endothelium-dependent vasodilation and reduced urinary nitrate excretion. This abnormality is reversed by administration of l -arginine. ADMA may be a novel risk factor for endothelial dysfunction in humans.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: VisualizationRole: Writing – original draft
                Role: InvestigationRole: MethodologyRole: Writing – original draft
                Role: Data curationRole: Investigation
                Role: Data curationRole: Investigation
                Role: Data curationRole: Investigation
                Role: InvestigationRole: MethodologyRole: Writing – original draft
                Role: Investigation
                Role: Formal analysis
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Investigation
                Role: Methodology
                Role: ConceptualizationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                22 May 2018
                2018
                : 13
                : 5
                : e0197148
                Affiliations
                [1 ] Department of Angiology, Wroclaw Medical University, Wroclaw, Poland
                [2 ] Department of Biochemistry, Wroclaw Medical University, Wroclaw, Poland
                [3 ] Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland
                [4 ] Department of Physiology, Wroclaw Medical University, Wroclaw, Poland
                [5 ] Department of Internal Medicine, Wroclaw Medical University, Wroclaw, Poland
                [6 ] Department of Mathematics, The Faculty Of Environmental Engineering And Geodesy, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
                [7 ] Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
                University of PECS Medical School, HUNGARY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-8087-8005
                Article
                PONE-D-17-26635
                10.1371/journal.pone.0197148
                5963779
                29787597
                b85b97f6-32aa-42d7-a678-d437f2fe00ef
                © 2018 Chachaj et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 16 July 2017
                : 28 April 2018
                Page count
                Figures: 1, Tables: 8, Pages: 14
                Funding
                Funded by: Wroclaw Medical University Grant
                Award ID: 18/Pbmn
                Award Recipient :
                The study was supported by Wroclaw Medical University, Grant number 18/Pbmn. The funding body accepted the study protocol and had no later influence on study performance, collection, analysis and interpretation of data, the writing of the manuscript or in the decision to submit the manuscript for publication.
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